Benzene-sulfonyl semicarbazides

ABSTRACT

Benzene-sulfonyl semicarbazides having hypoglycemic properties and corresponding to the general formula   WHEREIN R represents A. PHENYL WHICH MAY BE SUBSTITUTED ONCE OR TWICE BY SUBSTITUENTS OF THE GROUP LOWER ALKYL, ALKENYL, ALKOXY ALKENOXY, ALKOXYALKOXY, ACYL, HALOGEN, OR TRIFLUOROMETHYL, OR BY THE METHYLENE-DIOXY GROUP, B. THIENYL WHICH MAY BE SUBSTITUTED ONCE OR TWICE BY SUBSTITUENTS OF THE GROUP HALOGEN, LOWER ALKYL, ALKOXY, ALKENYLOXY, ALKOXYALKOXY, PHENALKOXY, OR ARYL, OR BY A POLYMETHYLENE CHAIN LINKED AT ITS TWO ENDS TO THE THIENYL GROUP, WHICH CHAIN CONTAINS FROM 3 TO 4 CARBON ATOMS; Y represents -CH2-CH2-, -CH2-CH-(CH3)- or -CH(CH3)-CH2; R1 represents A N-3-azaspiro-(5,5)-undecane AND SALTS THEREOF FORMED FROM PHARMACEUTICALLY ACCEPTABLE BASES.

United States Patent [:91

Weber ct al.

[ Oct. 22, 1974 BENZENE-SULFONYL SEMICARBAZIDES [75] Inventors: Helmut Weber, Frankfurt am Main; Walter Aumuller, Kelkheirn/Taunus;

Rudi Weyer, Frankfurt am Main; Karl Muth, KeIkheim/Taunus; Kurt Stach, Mannheim-Waldhof, all of Germany [73] Assignee: Farbwerke Hoechst Aktiengesellschaft vormals Meister [22] Filed: June 2, 1972 [21] Appl. No.: 259,300

Related U.S. Application Data [62] Division of Ser. No. 750.747, Aug. 7, 1968, Pat. No.

[30] Foreign Application Priority Data Aug. 12, 1967 Germany 53221 [52] U.S. CI. 260/293.66, 260/543 R, 260/556 AR [51] Int. Cl C07d 29/34 [58] Field of Search 260/293.66, 554

[56] References Cited UNITED STATES PATENTS 3,245,982 4/1966 McManus 260/247.l

FOREIGN PATENTS OR APPLICATIONS 1.478.953 3/1967 France 260/554 Primary Examiner-John D. Randolph Assistant Examiner-S. D. Winters Attorney, Agent, or FirmCurtis, Morris & Safford 5 7] ABSTRACT Benzene-sulfonyl semicarbazides having hypoglycemic properties and corresponding to the general formula wherein R represents a. phenyl which may be substituted once or twice by substituents of the group lower alkyl, alkenyl, alkoxy alkenoxy, alkoxyalkoxy, acyl, halogen, or trifluoromethyl, or by the methylene-dioxy group,

7 Claims, No Drawings 1 BENZENE-SULFONYL SEMICARBAZIDES Dec. 5, 1972.

The present invention provides benzene-sulfonyl semicarbazides of the formula and definition set forth in the Abstract. The new semicarbazides and their salts are valuable medicinal agents distinguished by a strong and particularly longlasting blood-sugar lowering activity.

The term lower always characterizes groups or radicals having 1 to 4 carbon atoms. There are especially preferable compounds wherein R represents a phenyl group substituted in 2-position by lower alkoxyor alkenoxy and in 4- or S-position by a halogen atom or by a lower alkyl or alkoxy.

The present invention further relates to a process for preparing said benzenesulfonyl semicarbazides. As methods for preparation, there may be mentioned the following methods:

a. Reaction of R-CO-NH-Y-substituted benzenesulfonamides, preferably in the form of their salts, with iminocarbamic acid esters, imino-thiolcarbamic acid esters, or imino-ureas containing as imino radical the group R,

b. reaction of hydrazines of the formula RNH or their salts with R-CO--NH-Y-substituted benzenesulfonyl isocyanates, benzenesulfonyl carbamic acid esters, benzenesulfonyl thiolcarbamic acid esters, carbamic acid halides or ureas,

c. reaction of RCO-NHY-substituted benzenesulfochlorides with R -substituted ureas or preferably with their salts,

d. hydrolysis of benzenesulfonyl-isosemicarbazide ethers, isothiosemicarbazide ethers or benzenesulfonyl-imino-parabanic acids,

e. exchange of the sulfur atom for an oxygen atom,

in benzenesulfonyl thiosemicarbazides of the formula f. introduction of the radical R-CO-, if desired in one or several steps, into benzenesulfonyl semicarbazides of the formula or by means of a bridge member such as CH NH-, -O-- or -S--, or N,N-disubstituted carbohydrazides of the formula R-NH-CONH-R.

Especially suitable as benzenesulfonyl carbamic acid halides are the chlorides.

Furthermore, corresponding benzenesulfonyl ureas which may be unsubstituted at the terminal nitrogen atom, or substituted once or twice by alkyl or aryl groups, may be converted into the final products by re acting these with hydrazines of the formula R-NH if desired, in the form of their salts. Instead of the benzenesulfonyl ureas substituted in this manner, there may be used the corresponding N-benzenesulfonyl-N- acyl ureas, benzene-sulfonyl-carbamoylimidazols, benzenesulfonyl-carbamoyl-pyrazols or benzenesulfonylcarbamoyl-triazols or bis-(benyenesulfonyl)-ureas which carry at one of the nitrogen atoms another substituent, for example methyl. Such bis- (benzenesulfonyl)-ureas or N-benzene-sulfonyl-N- acyl-ureas may be treated with hydrazines of the formula R'-NH and the salts obtained may be heated to elevated temperatures, preferably to at least C.

The imino-carbamic acid esters or benzenesulfonyl carbamic acid esters mentioned, as well as the corresponding thioesters, contain in the ester component preferably an alkyl radical of low molecular weight or a phenyl radical.

The benzenesulfonyl isosemicarbazide ethers, -isothiosemicarbazide ethers or -parabanic acids, used as starting materials, may be obtained by reacting corresponding isosemicarbazide ethers, isothiosemicarbazide ethers or parabanic acids with corresponding benzenesulfochlorides. Benzenesulforlyl isosemicarbazide ethers are also obtained, in the first place, by desulfurizing benzenesulfonyl thiosemicarbazides in methanol. They are subsequently converted into benzenesulfonyl semicarbazides by hydrolysis.

Depending on the nature of the member R--CO--, in some cases, the one or the other of the previously described methods may prove unsuitable for preparing the individual compounds falling underthe general formula, or at least will make it necessary for active groups to be protected. Such relatively rare cases can easily be recognized by the expert, and there is no difficulty insuccessfully applying another one of the syntheses described.

As regards the reaction conditions, the process embodiments of the present invention may in general, vary within wide limits and may be adapted to each individual case. For example, the/reactions can be effected with the use of solvents, at room temperature or at an elevated temperature.

'As starting substances there are used, as one reactant, compounds containing a benzene radical substituted by the group R-CO--NH-Y--. As radical R may be mentioned, for example, the following groups:

F F v ()H;

01 i B r F CH; (ion, (ion, (ion,

on, o1

OH; OCH:

OCHz-CH=CH2 The sulfonyl-semicarbazide derivatives obtainable according to the present invention, are valuable medicinal agents which are distinguished by a strong action of lowering the blood sugar level. This applies, in particular, to such compounds in which R represents a phenyl radical carrying an alkoxy group in 2-position. The blood sugar lowering action of the products of the invention could be ascertained, for example, in rabbits, by administering the compounds in a dose of mg/kg and by determining the blood sugar value, over a prolonged period of time, according to the known method of Hagedorn-Jensen. The following table comprises the blood sugar lowering activities of some of the compounds obtained according to the process of the pres .ent invention:

TABLE Limit amount causing lowering Lowering of the blood sugar level CHQ 01-Q- 3 0 H3 CHBO l CaH70 in contradistinction thereto, the [N-(4-methylbenzenesulfonyl)-N'-n-butyl-urea] known as antidiabetic and used as medicinal agents shows no lowering of the blood sugar level when administered in a dose of 25 mg/kg in a comparative test.

The toxicities of the products of the invention are very low, they are within the range of the abovementioned N-(4-methyl-benzenesulfonyl)N'-n-butylurea which is very well tolerable.

It is preferable to process the products of the present invention into orally administerable preparations which have blood sugar lowering action and which can accordingly be used in the treatment of diabetes mellitus; these can be employed as such or in the form of their salts or in the presence of substances causing salt formation. For such salt formation there can be used, for example, alkaline agents such as alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates and alkaline earth metal bicarbonates or physiologically tolerated acids. The pharmaceutical preparations are preferably in the form of tablets which contain, in addition to the compounds of the present invention, the usual adjuvants and carriers such as talc, starch, lactose, tragacanth, magnesium stearate and the like.

The following Examples serve to illustrate the present invention, but these are not intended to limit it thereto:

Eitample l benzenesulfonyl]-methylurethane (melting point l78l80C) 4-[4-([3- 3-trifluoromethylbenzamido -ethyl)- benzenesulfonyl1-l l-(2.5-endethylene-hexamethylene)-semicarbazide of the melting point l93l 95C (from methanol);

from N-[4-(B- 3-chlorobenzamido -ethyl)- benzenesulfonyl]-methyl-urethane (melting point l73l75C) 4-[4-(B- 3-chlorobenzamido -ethyl)- benzenesulfonyl ]-l l-( 2.5-endoethylene-hexamethylene)-semicarbazide of the melting point l98-200C (from methanolldimethylformamide); from N-[4-(B- 3-methoxythiophene-2- carbonamido -ethyl)-benzenesulfonyl]- methylurethane (melting point 226-228C) 4-[4-(B- 3-methoxythiophene-2-carbonamido ethyl)-benzene-sulfonyl]-l l-(2.5- endoethylenehexamethylene)semicarbazide, melting point l66-l68C (from methanol);

from N -[4-(,8- 3.4-dichlorobenzamido -ethyl)- benzenesulfonyll-methylurethane (melting point l98-200C) 4-[4-(B- 3.4 dichlorobenzamido -ethyl)- benzenesulfonyl l .l (2.5-endoethylene-hexamethylene)-semicarbazide, melting point (from methanol/dimethylformamide); from N-[4-(B- 3.5-dimethylthiophene-2- carbonamido -ethyl)-benzenesulfonyl]- methylurethane (melting point l7()l72C) 4-[4-(B- 3-5-dimethylthiophene-Z-carbonamido ethyl )-benzenesulfonyl]- l l (2.5-endoethylenehexamethylene)-semicarbazide, melting l84-l 86C (from methanol);

point from N-[4-(B- 2-methoxybenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point l74-l76C) 4-[4-(fl- 2-methoxybenzamido -ethyl)- benzenesulfonyl l l-(2.5-endoethylene-hexamethylene)-semicarbazide, melting point I50-l52C (from methanol);

from N-[4-(B- 2 -methoxy--methyl-benzamido ethyl)-benzenesulfonyl]-methylurethane (melting point l75-l77C) 4-[4-(,8- 2methoxy-5-methylbenzamido -ethyl)- benzenesulfonyl1- l l (2.5-endoethylene-hexamethylene)-semicarbazide, melting point (from methanol);

from N-[4-(fl- 2-methoxy-S-bromo-benzamido ethyl)-benzenesulfonyl]-methylurethane (melting point l97-l99C) 4-[4-(B- 2-methoxy-5-bromobenzamido -ethyl)- benzenesulfonyl ]-l 1-( 2.5-endoethylene-hexamethylene)-semicarbazide, melting point l-l87C (from methanol);

from N-[4-(B- 2-ethoxy-5-chlorobenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point 203205C) 4-[4-(B- 2-ethoxy-5-chlorobenzamido -ethyl)- benzenesulfonyl1- 1 l-( 2.5-endoethylene-hexamethylene)-semicarbazide, melting point l96l98C (from methano/dimethylformamide);

from N-[4-(B- 3.S-dimethylbenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point 223-225C) 4-[4-(/3- 3.5-dimethylbenzamido -ethyl)- benzenesulfonyH-l l-(2.5-endoethylene-hexamethylene)-semicarbazide, melting point 2ll-2l3C (from methanol/dimethylformamide);

from N-[4-(fl- 2-ethoxy-5-fluorobenzamido -ethyl)- benzenesulfonyll-methylurethane (melting point l93-l95C) 4-[4-(B- 2-ethoxy-5-fluorobenzamido -ethyl)- benzenesulfonyl]- l I-( 2.5-endoethylene-hexamethylene)-semicarbazide, melting point l6l-l63C (from methanol);

from N-[4-( 8- 2-ethoxy-5-acetylbenzamido -ethyl)- benzenesulfonyll-methylurethane (melting point l64-l66C) 4-[4-(B- 2-ethoxy-5-acetylbenzamido -ethyl)- benzenesulfonyH-l l-( 2.S-endoethylene-hexamethylene)-semicarbazide, melting point l96l98C (from methanol);

from N-[4-(B- 3-chlorobenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point l73l75C) N-[4-(fl- 3-chlorobenzamido -ethyl)- benzenesulfonyl]-N-(decahydro-quinolino)'urea, melting point 245-247C (decomposition) (from methanol/dimethylformamide);

from N-[4-(B- 3-ethoxythiophene-Z-carbonamido ethyl)-benzenesulfonyl]-methylurethane (melting point 163l65C) N-[4-(B- 3-ethoxythiophene-2-carbonamido -ethyl)- benzenesulfonyl]-N decahydroquinolino-urea, melting point 186-l87C (from methanol/dimethylformamide);

from N-[4-(,8- Z-methoxybenzamido -ethyl)- benzenesulfonyl]-methylurethane (melting point l74-l76C) N-[4-(B-(2-methoxybenzamido -ethyl)- benzenesulfonyl]-N'-decahydroqu.inolino-urea, melting point 205-206C (from methanol/dimethylformamide);

from N-[4(,8- 2-methoxy-S-chlorobenzamido ethyl )-benzenesulfonyl]-methylurethane (melting point l93-l94C) N-[4([32-methoxy-5-chlorobenzamido-ethyl)- benzenesulfonyl]-N'-decahydroquinolino-urea, melting point 2l8-219C (from methanol/dimethylformamide) and N-[ 4-( B- 2-methoxy-5-chlorobenzamido -ethyl benzenesulfonyl]-N-tetrahydroisoquinolino-urea, melting point l48150C (from methanol); from N-[4-([3- 2-methoxy-5-methylbenzamido ethyl)-benzenesulfonyl]-methylurethane (melting point 175-177C) N-[4 (B- 2-methoxy-S-methylbenzamido -ethyl)- benzenesulfonyl]-N'-decahydroquinolino-urea, melting point 200202C (from methanol/dimethylformamide) and N-[4(B- 2-methoxy-5-methylbenzamido -ethyl)- benzenesulfonyl]-N-tetrahydroisoquinolino-urea, meltingpoint 182-184C (from methanol/dimethylformamide); from N-[4-(13-3-methoxy-5-chlorothiophene-2- carbonamido-ethyl)-benzenesulfonyl]-methylurethane (melting point l86l88C) N-[4 (B- 3-methoxy-5-chlorothiophene-2- carbonamido -ethyl)-benzenesulfonyl]-N'- tetrahydroisoquinolino-urea, melting point l77l 79C (from methanol/dimethylformamide); from N-[4-(B- 2-methoxy-4- trifluoromethylbenzamido -ethyl)-benzenesulfonyl]- methylurethane (melting point 190192C) N-[4-(,B- 2-methoxy-4-trifluoromethylbenzamido ethyl )-benzenesulfonyl]-1 l (2.5-endoethylenehexamethylene)-semicarbazide, melting point 172174C (from methanol);

from N-[4-(B- 2-methoxy-benzamido -ethyl)- benzenesulfonyll-ethylurethane (melting point 144C) N-[4-(B- 2-methoxy-benzamido -ethyl)- benzenesulfonyl]-N'-(3-azaspiro-[5,5]-undecyl-3)- urea (melting point 187-l88C);

from N-[4-(B- 2 methoxy-S-chloro-benzamido ethyl )-benzenesulfonyl]-methylurethane (melting point l78-l79C) N-[ 4-( B- 2-methoxy-5-chloro-benzamido -ethyl benzenesulfonyl]-N'-(3-azaspiro-[5,5]-undecyl-3)- urea (melting point 166l69C) and N-[4(B- 2-methoxy-5-chloro-benzamido -ethyl)- benzenesulfonyl]-N'-(N-thiomorph0lyl)-urea (melting point 194-196C);

from N-[4-(B- 2-methoxy-5-methyl-benzamido ethyl)-benzenesulfonyll-ethylurethane (melting point l66-l70C) N-[4-(B- 2-methoxy-5-methyl-benzamido -ethyl)- benzenesulfonyl]-N'-3-azaspiro-[5,5]-undecyl-3)-urea (melting point 17l-173C);

from N-[4-(B- 2-methoxy-5-fluoro-benzamido ethyl)-benzenesulfonyl]-ethylurethane (melting point 123C) N-[4-(B- Z-methoxy-5-fluoro-benzamido -ethyl)- benzenesulfonyl]-N'-(3-azaspiro-[5,5]-undecyl-3)- urea (melting point 173C);

from N- 4-( B-benzamido-ethyl )-benzenesulfonyl]- methylurethane (melting point 186C) N-[4-(B-benzamidoethyl)-benzenesulfonyl]-N'-(3- azaspiro-[5,5]-undecyl-3)-urea (melting point 186-187C);

from I N-[4-( [3- 3-chloro-benzamido -ethyl benzenesulfonyl]-methylurethane (melting point 174-176C) N-[4-(,B- 3-chloro-benzamido -ethyl)- benzenesulfonyl]-N-(3-azaspiro-[5,5]-undecyl-3)- urea (melting point l83l84C).'

Example 2 N-[4-(B- 2-methoxy-5-chlorobenzamido -ethyl)- benzenesulfonyl]-N'-(4,7-methano-hexahydro-isoindolino-2)-urea 12.8 Grams of N- [4-( B-Z-methoxy-S chlorobenzamido-ethyl)-benzenesulfonyl]-methylurethane were dissolved in 150 milliliters of dioxane. While stirring 4.6 grams of N-amino-4,7-methanohexahydro-iso-indoline were added thereto and the whole was heated to 100C for 1.5 hours while stirring was continued. After dioxane had been distilled off in vacuo, the residue was dissolved in dilute ammonia (1:25), filtered and acidified with dilute acetic acid. The N-[4-(l3- 2-methoxy-5-chlorobenzamido ethyl)-benzenesu1fonyl]-N-(4,7-methano-hexahydroiso-indolino-2)-urea thus obtained melted at l63165C after recrystallization from dilute methanol/dioxane.

In an analogous manner there were obtained from the corresponding sulfonyl-urethane l. N-[4-(B-benzamido-ethyl)-benzenesulfonyl]-N- (4,7-methano-hexahydro-isoindolino-2 )-urea, melting point 190-192C (from dilute methanol/dioxane); I

2. N-[4-( 8- 4-ch1oro-benzamido -ethyl)- benzenesulfonyl]-N'-(4,7-methano-hexahydroisoindolin0-2)-urea, melting point 203.5 3O 205.5C (from dilute methanol/dioxane);

3. N-[4-(B-thiophene-Z-carbonamidoethyl)- benzenesulfonyl]-N-(4,7-methano-hexahydroisoindolino-2)-urea, melting point 229-231C (from dilute methanol/dioxane);

4. N-[4-(B- 5-chloro-thiophene-2-carbonamido ethyl )-benzenesulfonyl -N 4,7-endomethylenehexahydro-isoindolino-2)-urea, melting point 173-175C;

5. N-[4-(B-benzamido-ethyl)-benzenesulfonyl]-N'- (3,6-endoethylene-hexamethylene-imino)-urea, melting point 191-193C.

We claim:

1. A benzene-sulfonyl semicarbazide of the formula urea.

6. The compound as defined in claim 1, wherein the same is N-[4-(B- 2-methoxy-5-chloro-benzamido ethyl)-benzenesulfonyl]-N'-(3-azaspiro-[5,5]-undecyl- 3)-urea.

7. The compound as defined in claim 1, wherein the same is N-[4-(B- 2-methoxy-ibenzamido -ethyl)- benzenesulf0nyl1-N 3-azaspiro-[ 5,5 ]-undecyl-3 urea. 

1. A BENZENE-SULFONYL SEMICARBAZIDE OF THE FORMULA
 2. A benzene-sulfonyl semicarbazide as claimed in claim 1, wherein R represents phenyl substItuted in 2-position by lower alkoxy.
 3. A benzene-sulfonyl semicarbazide as claimed in claim 1, wherein R represents phenyl substituted in 2-position by lower alkoxy and in 4- or 5-position by halogen, lower alkyl or lower alkoxy.
 4. A benzene-sulfonyl semicarbazide as claimed in claim 1, wherein R represents phenyl substituted in 2-position by methoxy and in 5-position by halogen or methyl.
 5. The compound as defined in claim 1, wherein the same is N-(4-( Beta -<3-chloro-benzamido>-ethyl)-benzenesulfonyl)-N''-(3-azaspiro-(5,5)-undecyl -3)-urea.
 6. The compound as defined in claim 1, wherein the same is N-(4-( Beta -<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl)-N''-(3-azaspiro-(5,5)-undecyl-3)-urea.
 7. The compound as defined in claim 1, wherein the same is N-(4-( Beta -<2-methoxy-benzamido>-ethyl)-benzenesulfonyl)-N''-(3-azaspiro-(5,5)-undecyl -3)-urea. 